Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell-mediated destruction of the insulin-producing ? cells in the pancreatic islets. Several T1D-associated class I MHCs have been identified, including HLA-A*0201, expressed by many T1D patients; ? cell epitopes restricted to this MHC have been identified as well. We hypothesize that these ? cell epitopes may be utilized as part of immunomodulatory therapies to prevent the onset of T1D. This may be done by utilizing the dendritic cell (DC) endocytic receptorDEC-205. In the absence of adjuvant, epitopes delivered via DEC-205 are presented to T cells in a tolerogenic manner, resulting in T cell tolerance towards those epitopes. Our laboratory has shown that when murine ? cell epitopes linked to anti-murine DEC-205 are delivered to DCs in vivo, T cells specific for those epitopes are deleted in non-obese diabetic (NOD) mice. We will further these studies in humanized mouse models. Importantly, while only a subset of murine DCs expresses DEC-205, it is present on all human myeloid DCs; our model replicates the human case via expression of human DEC-205 on all murine myeloid DCs. We hypothesize that, as with anti-murine DEC-205 treatments, the delivery of murine ? cell epitopes via antibodies against human DEC-205 will also induce T cell tolerance. Previous studies have also shown that simultaneous delivery of several HLA-A*0201-restricted ? cell epitopes, chemically linked to splenocytes, to HLA-A*0201-transgenic NOD mice prevented the onset of diabetes. To develop more clinically relevant reagents, we will simultaneously deliver these epitopes to NOD mice transgenic for both human DEC-205 and HLA-A*0201; we expect the induction of T cell tolerance towards these epitopes and prevention of T1D. This has the potential to aid the many T1D patients who express HLA-A*0201. However, HLA-A*0201 is not expressed by all T1Dpatients. To develop treatments for these patients, other T1D-associated class I MHCs should be considered, including the early onset-associated HLA-B*3906. While HLA-B*3906 is itself a rare allele, we have shown it to be a member of the HLA-B27 super type, whose members are expressed by 28% of the population. Studying HLA-B*3906 has the potential to have a large impact as peptides presented by one super type member are often capable of being presented by another. Our preliminary studies suggest that expression of HLA-B*3906in NOD mice results in the acceleration of T1D. To further examine the effect of HLA-B*3906 on T1D, we will also determine the effect of HLA-B*3906 on T1D incidence in NOD mice lacking murine class I MHC. A similar model has been used to identify HLA-A*0201-restricted ? cell epitopes, a method we will apply to HLA-B*3906.To do so, we will map potential epitopes from both human and murine ? cell antigens. These epitopes could then be used in future immunomodulatory therapies.